Ambulatory 2 Rad

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Abbreviations

AF = atrial fibrillation; ASA = acetylsalicylic acid; CAD = coronary artery disease

CHF = chronic heart failure; CV = cardiovascular

DVT = deep venous thrombosis; E F = ejection fraction; H TN = hypertension

INR = International normalized ratio; L A = left atrial ; LV = left ventricular

LMWH = low-molecular-weight heparin; MI = myocardial infarction;

PE = pulmonary embolism; TIA = transient ischemic attack

FFP = fresh frozen plasma; VKA = vitamin K antagonist

MVP = mitral valve prolapse , MVR= replacement, AVR= aortic valve replacement

UFH= unfractionated Heparin



INR2-3

1. Inhibits vitamin Kdependent clotting factors II, VII, IX, and X

2. Inhibits anticoagulant proteins C and S**


1.Venous Thromboembolism (VTE): DVT or PE

*Rivaroxaban is also now indicated for VTE treatment

Low risk: 0 RF, moderate risk: 1 RF, high risk 2 RFs (bleeding risk from each risk factor depends on the severity of the RF, the time interval, and whether RF was corrected)

Time-limited RF: 1. Surgery2. immobilization3. Estrogen4. pregnancy For all acute DVTs, bridging therapy is preferred (1B). If LMWH used, once daily suggested over twice daily (2C)

1. DVT/PE with reversible or time-limited risk factor.

2. 2.5 (23) 3. 1A 4. 3 months

At least 3 months; then evaluate for risk-benefit ratio of extended therapy. Proximal DVT or PE: 1. If low-moderate bleeding risk

:Extended VKA (2B) 2. If high risk: 3 months of VKA(1B)

First unprovoked PE or proximal DVT 1A


1. Elderly(Age > 65)2. previous Bleeding3. cancer, metastatic cancer4. Abnormal)renal failure, liver failure thrombocytopenia)5. previous Stroke6. Diabetes7. Anemia8. Drug)antiplatelet therapy)9. Labile INR)poor anticoagulant control)10. recent surgery11. frequent falls12. Drug)alcohol abuse)


2.CAD/Acute MI

without stentingVKA plus ASA (75100 mg/day) for first 3 months (1B)

3monthes of VKA ((thrombus

Then DC and switch to dual

antiplatelettherapy for up to

12 months, followed by

single antiplatelet

therapy(stent)

Anterior MI and LV thrombus, orhigh risk of LV thrombus(EF < 40%, anteroapicalWMA)

BMSTriple therapy (warfarin, ASA, clopidogrel) for 1 month; then warfarinplus single antiplatelet agent for 2

months

DESTriple therapy (warfarin, ASA, clpidogrel) for 36 months


3.Conversion of Atrial Fibrillation

Other (equal) options: dabigatran or LMWH (treatment dose). At least 3 weeks before and at least 4 weeks after sinus rhythm maintained.

1. Elective direct current cardioversion of AF 48 hours or unknown duration

2. 2.5 (23) 3. 7 weeks 4. 1C


4.Valvular Heart Disease

Rheumatic MVD in sinus rhythm if Dilated LA))LA diameter is > 55 mm

Rheumatic Mitral Valve Disease with history of systemic embolim, LA thrombus,Or AF

Warfarin2.5 (23) Long term 2C

Warfarin2.5 (23) Long term 1A


5.Mechanical and Bioprosthetic Heart Valves

Warfarin (2-3) 3 monthsthen switch to ASA 50100 mg/ day if normal sinus rhythm

Mitral Bioprosthetic heart valve

normal sinus rhythm: ASA 50100 mg/day

(no warfarin) Aortic

Add ASA (50100 mg/day) if low risk of bleeding (1B)

Warfarin2.5 (23)Long term 1B

Mechanical prosthetic heart valve: aortic

Warfarin

3 (2.53.5) Long term 2C

Mechanical prosthetic heart valve: Mitral



1.a 30 y/o woman receiving warfarin for aproximal DVT. She was taking oral contraceptives at the time her DVT was diagnosed;they have since been discontinued. Which of the following is correct with regards to recommended duration of warfarin?A. 3 monthsB. 6 monthsC. 1 yearD. Indefinite

2.a 63 y/o woman with Mechanical Mitral valve replacement(MVR)3. Mechanical AVR, HTN, dyslipidemia. Meds:warfarin 8 mg/d, aspirin 81 mg/d, lisinopril, atorvastatin. What is M.H.s goal INR?A. 1.5 2.5B. 1.8 2.6C. 2 3D. 2.5 3.5

Specific patients may need a lower starting dose (5 mg/day or, in some cases, 23 mg/day).

i. Elderly ii. Very low body weight iii. Concurrent interacting drug (enzyme inhibitor) iv. Malnourished or nothing by mouth for more than 3 days v. Liver disease vi. Congestive heart failure vii. High risk of bleeding viii. Prolonged fever ix. Hyperthyroid state x. Low albumin


a.fully inhibit factor II b.prevent possible activation with rapid depletion of protein C

and S until INR is therapeutic for at least 24 hours.

a. Begin warfarin on day1(preferred)or day2 of UFH or LMWH. b. CHEST guidelines suggest initiating warfarin at 10 mg/day

for the first 2 days, followed by INR-based dosing (2C). Otherwise, 5 mg/day is generally sufficient.


a.INR seen today is the result of the doses given during the past 45 days. Takes 57 days to reach full effect, given the half-life of factor II

b. Half-lives of vitamin Kdependent clotting factors VII = 6 hours

IX = 24 hours

X = 36 hours


I. If INR is high, hold 1-2 doses, resume at lower dose

II. No need to adjust dose if INR is within 0.1 of goal (monitor closely)

III. 2012 CHEST guidelines single out-of-range INR is 0.5 above or below goal,continue current dose and recheck INR within 1-2 weeks (2C)


1. bridging with LMWH/UFH for a single subtherapeutic INR in a patient normally stable (2C).

2. routine use of vitamin K supplementation (2C).

3. routine use of pharmacogenetic testing to guide the dosing of warfarin (1B).


1. Bleeding

Epistaxis, hematuria,GI hemorrhage, bleeding gums ,easy bruising often with therapeutic INR.

2. Skin necrosis (rare)

3. Purple toe syndrome (rare),

4. Teratogenicity (category X)

SC.heparin or LMWH is safe.


i. HTN (1 point) ii. Abnormal renal/liver function (1 or 2 points; 1 point each) iii. Stroke (1 point) iv. Bleeding history or predisposition (1 point) v. Labile INR (1 point) vi. Elderly (age older than 65 years) vii. Drugs (concomitant antiplatelet/NSAID use) and/or EtOH abuse (1 or

2 points; 1 point each)


1. Reduced warfarin absorption (e.g., cholestyramine, sucralfate)

2. Enzyme induction (decreases INR and warfarineffects) a. CYP3A4 (e.g., rifampin, carbamazepine, phenobarbital, St.

Johns wort) b. Other (e.g., griseofulvin, nafcillin, dicloxacillin, phenytoin

[inhibition; then induction])

c. Delay in onset


3. Enzyme inhibition (increases INR and warfarin effects)

a. S-warfarin* (CYP2C9) (e.g., metronidazole, trimethoprim/sulfamethoxazole, fluconazole, isoniazid, fluoxetine, sertraline, amiodarone, clopidogrel, lovastatin)

b. R-warfarin (CYP3A3/4/5) (e.g., omeprazole, clarithromycin, erythromycin, azole antifungals, nefazodone, fluoxetine, amiodarone, cyclosporine, sertraline, grapefruit juice, ciprofloxacin, norfloxacin, protease inhibitors, diltiazem, verapamil, isoniazid, metronidazole)

4. Antiplatelet effects NSAIDs and aspirin also increase the risk of ulcers, providing a site from which to bleed.


5. Reduced clearance of warfarin (e.g., propafenone)

6. Increased degradation of clotting factors (e.g.,levothyroxine)

7. CHEST guidelines recommend avoidingconcomitant NSAIDs (including COX-2 inhibitors) and antibiotics (2C). Antibiotics with evidence of increased risk of bleeding: Trimethoprim/sulfamethoxazole, quinolones, metronidazole, cephalosporins, doxycycline,

amoxicillin.


Action Situation INR

Recommend against routine vitamin K Omit one or two doses of warfarin, and monitor INR more often. Restart warfarin at a lower dose when the INR is in the therapeutic range

No evidence

of bleeding

4.5-10

Omit the next several warfarin doses and give oral vitamin K1 (510 mg). Monitor INR closely and repeat vitamin K1, if necessary. Resume warfarin at a lower dose when INR is in the desired range

More than 10

Hold warfarin, give vitamin K1 510 mg by slow IV injection plus prothrombin complex concentrate (recommended over FFP).

If needed, repeat vitamin K1 injection every 12 hours

VKA-associated major bleeding

FFP = fresh frozen plasma; INR = international normalized ratio; IV = intravenous; VKA = vitamin K antagonist.


foods with Medium-High Vitamin K Content: Green vegetables, Liver, Green tea.

:May result in increased INR and a lower warfarin dose requirement 1. Malnourished/nothing by mouth 2. Recent major surgery 3. Chronic heart failure (especially acutely decompensated) 4. Liver disease 5. Hyperthyroid state (increased clearance of clotting factors) (opposite

occurs in hypothyroid state) 6. Prolonged fever (increased clearance of clotting factors) 7. Diarrhea


a. Mild: Nosebleeds, bleeding gums, easy bruising

b. More severe: Hematuria, hematemesis, hemoptysis, melena, bright red blood per rectum.

= (PTpatient/PTmean), PT = prothrombin time.a. In general, check INR within 12 weeks after dose

adjustment.

c. Latest CHEST guidelines state that if INR is consistently stable, suggest INR testing frequency of up to 12 weeks (2B)



A 79-year-old man is taking warfarin 5 mg/day for atrial fibrillation. His other conditions are depression and gastroesophageal reflux disease. His medications include fluoxetine 20 mg (started 1 month ago) and omeprazole 40 mg/day (started 6 months ago). He has warfarin 5-, 2-, and 1-mg tablets at home. His INR was last checked 6 weeks ago and was in range at that time. He denies any signs or symptoms of bleeding. You check his INR, and it is 8.

A. Hold warfarin for 1 day and then reinitiate it at a lower dose (no need to recheck INR). B. Hold warfarin for 2 days and then reinitiate it at a lower dose (no need to recheck INR). C. Hold warfarin for 2 days, recheck INR, and reinitiate warfarin at a lower dose when INR approaches 3. D. Hold warfarin, give oral vitamin K 2.5 mg for 1 day, and reinitiate warfarin at a lower dose when INR approaches 3.

A. 5 mg 2 days/week and 2.5 mg 5 days/week. B. 2.5 mg/day. C. 4 mg/day. D. 4.5 mg 2 days/week and 5 mg 5 days/week.

a. Pregnant woman receiving anticoagulation for VTE should be switched to LMWH (not UFH).

Avoid dabigatran, rivaroxaban, and apixaban.

b.Pregnant woman with acute VTE, Anticoagulant should be continued for at least 6 weeks postpartum (for a minimum total therapy duration of 3 months).


c. If a woman with a mechanical heart valve becomes pregnant:

i. Use adjusted-dose twice-daily LMWH or UFH throughout pregnancy OR

ii. Use adjusted-dose twice-daily LMWH or UFH until 13th week of pregnancy; then switch to warfarin; then switch back to LMWH or UFH close to delivery



6.A 30-year-old pregnant woman had a DVT during her pregnancy at36 weeks,7.26 weeks.She received low-molecular-weight heparin (LMWH) until delivery(at 40 weeks). She has now delivered a healthy baby boy, whom she is breastfeeding. Which best represents how long she should now receive warfarin, after delivery? A. Warfarin is C.I in women who are breastfeeding; continue LMWH. B. Warfarin should be used for 6 weeks. C. Warfarin should be used for 3 months. D. Warfarin should be used for the rest of her life.

can be safely used while a woman is breastfeeding; use these rather than dabigatran, rivaroxaban, or apixaban.

1. Stop warfarin approximately 5 days before surgery

2. In 2 days, start therapeutic dose LMWH

3. Give last dose of LMWH 24 hours before surgery

4. IV UFH 46 hours before surgery

5. consider half dose if using once-daily LMWH

6. Check INR day before surgery if feasible; give 1-2 mg vitamin K if INR 1.5

7. Post-op, commence

LMWH (24 hr after minor surgery;

48-72 hr if major surgery/high bleeding risk) and

warfarin (12-24 hr after surgery)

8. Continue LMWH until warfarin therapeutic



8.A 77 y/o man with AF, HTN, diabetes, and h/o TIA 3 years ago. Having major abdominal surgery in 1 week and will need to hold his warfarin. Which of the following is the most appropriate LMWH bridge therapy?A. No bridge LMWH is needed; just hold warfarinB. Enoxaparin 30 mg BIDC. Enoxaparin 1mg/kg BIDD. Either enoxaparin 30 mg BID or 1 mg/kg BID are options

9.A 65-year-old man is taking warfarin for a DVT 2 months ago. He will be undergoing major abdominal surgery in 1 week and will need to hold his warfarin.Which is the most appropriate LMWH bridge therapy for him? A. No bridge LMWH is needed; just hold warfarin. B. Administer enoxaparin 30 mg twice daily. C. Administer enoxaparin 1 mg/kg twice daily. D. Enoxaparin either 30 mg twice daily or 1 mg/kg twice daily is an appropriate option.

Bileaflet aortic valve without AF or other RFs. for stroke

Bileaflet aortic valve and one or more RFs

Any mechanical mitral valve, older aortic valve (caged ball, tilting disk)recent stroke/TIA (past 6mo.)

CHADS2 score 02 and no previous stroke/TIA

CHADS2 score 3 or 4 CHADS2 score of 5 6recent stroke/TIA (past 3mo.) Rvh disease.

VTE more than 12 months ago with no risk factors

VTE in the past 312 months, non severe thrombophilic cond.

Recent VTE (past 3 mo.)severe thrombophiliaeg.(dec in prot. C,S)


(single- or multi-tooth extractions or root canal) suggest continuing VKA and using oral pro-hemostatic agent (aminocaproic or tranexamic acid mouthwash) or discontinuing VKA 23 days before procedure (2C).

suggest continuing VKA and using local measures (2C)


a. Consider using UFH instead of LMWH in severe CKD.

b. Very limited data with LMWH in patients with CrCl less than 20 mL/minute or on hemodialysis

c. Enoxaparin is the LMWH best studied in CKD; preferred agent

d. Prophylaxis of VTE:in severe CKD, recommended enoxaparin dose is 30 mg once daily.


1.If LMWH is used in patients with severe CKD

(CrCl less than 30 mL/minute),

Recommended to use 50% of the usual dose of enoxaparin

(e.g., 1 mg/kg once daily for therapeutic dose or bridging)

2.Strongly consider UFH in patients with a CrCl less than 20 mL/minute or on hemodialysis.

3.Consider anti-Xalevel monitoring in severe CKD


increase dose by 30% in morbidly obese patients ([BMI] of 40 kg/m2 or greater).

i. Weight-based dosing should use actual body weight in obese patients (BMI greater than 27 kg/ m2), up to a max. of 190 kg. Enoxaparin: Twice-daily dosing should be used with no dose capping (maximum dose).

ii. BMI greater than 40 kg/m2 or weight greater than 190 kg,consider initiating dosing according to actual body weight and monitoring anti-Xa levels with dose adjustment, if required.

iii. Some recommend using UFH in very obese patients.


: LMWH, fondaparinux,apixaban,dabigatran,rivaroxaban,

low-dose UFH, adjusted-dose VKA, or aspirin (all 1B), or

Intermittent pneumatic compression device (IPCD) (1C),

are recommended for a minimum of 1014 days ,preferred 35 day in major orthopedic surgury. LMWH preferred to other agents.

If patients decline injections, apixaban or dabigatran(1B) are recommended over other agents. Rivaroxaban or VKA is recommended next.



10.A 68-year-old man presents with a second unprovoked DVT. His first unprovoked DVT was 3 years ago, at which time he completed 3 months of warfarin therapy. He has hypertension, diabetes, and CKD (CrCl 25 mL/minute). Which is the most appropriate management of this DVT? A. Enoxaparin 1 mg/kg twice daily initially; then warfarin indefinitely. B. Enoxaparin 1 mg/kg once daily initially; then warfarin for 3 months. C. Enoxaparin 1 mg/kg twice daily initially; then rivaroxabanindefinitely. D. Enoxaparin 1 mg/kg once daily initially; then rivaroxaban for 3 months.

a. Oral direct thrombin inhibitor (DTI)

b. Indicated only for the prevention of stroke and systemic embolism in patients with nonvalvular AF.

c. Dose:

150 mg orally twice daily

CrCl 1530 mL/minute: 75 mg twice daily.

e. Contraindications: Active pathologic bleeding; hypersensitivity to dabigatran; mechanical prosthetic heart valve (new C.I December 2012); not recommended for bioprosthetic heart valves


f. Drug interactions:

i. Avoid using dabigatran with P-glycoprotein (Pgp) inducers (e.g., rifampin), which reduce exposure to dabigatran.

ii. Concomitant Pgp inhibitors: Consider reducing dose to 75 mg twice daily if concomitant ketoconazole or dronedarone and CrCl 3050. Avoid dabigatran with CrCl less than 30 and Pgp inhibitors above plus verapamil, amiodarone, clarithromycin, and quinidine.

iv. Surgery/reversal:

(a) Discontinue dabigatran 12 days (CrCl of 50 mL/minute or greater) or 35 days (CrCl less than 50 mL/minute) before procedure. Consider a longer time for major surgery or spinal puncture/catheter.

(b) No antidote; can be removed by hemodialysis, but limited experience


a. Oral direct factor Xa inhibitor

. Clinical studies show superiority to enoxaparin, with no difference in major bleeding events.

i. Dose: 10 mg orally once daily, starting at least 610 hours after surgery.

CrCl less than 30 mL/minute: AVOID

ii. Duration: 35 days for hip replacement

12 days for knee replacement


. Dose:20 mg orally OD with evening mealCrCl 1550 mL/minute: 15 mg OD.CrCl less than 15 mL/minute: AVOID

. Dose:15 mg orally twice daily for first 21 days after

event; then 20 mg orally once daily for remaining treatment (studied for 6 months of treatment) and long-term reduction in risk of recurrent DVT/PE.

CrCl less than 30 mL/minute: AVOID


Active major bleeding, hypersensitivity, severe CKD, moderate-sever hepatic impairment, or any hepatic disease associated with coagulopathy

i. Increased risk of thromboembolic events with discontinuation without other anticoagulant coverage

ii. Bleeding iii. Moderate CKD (CrCl from 30 mL/minute to less than 50

mL/minute): Closely observe for signs of bleeding. v. Severe hepatic impairment: Avoid in moderate to severe

hepatic impairment. vi. Prosthetic heart valves: not recommended.


:

i. Avoid concomitant use with combined Pgp and strong CYP3A4 inhibitors

ii. Avoid concomitant use with combined Pgp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. Johns wort).

iii. Use in patients with CrCl 1550 mL/minute receiving concomitant combined Pgp and weak or moderate CYP3A4 inhibitors

(a) Discontinue rivaroxaban at least 24 hours before the procedure, and reinitiate it after the procedure as soon as adequate hemostasis is established.

(b) Short half-life (59 hours), so reversal and re-anticoagulation occur quickly

(c) No antidote; not expected to be dialyzable


a.Oral direct factor Xa inhibitor b. Reduction of the risk of stroke and systemic

embolism in patients with nonvalvular AF. c

exist1. age 80 or older2. body weight of 60 kg or less3. serum creatinine of 1.5 mg/dL or greater

of CYP3A4 and Pgp


i. Increased risk of stroke with discontinuation in AF

ii. Bleeding

iii. Prosthetic heart valves ,not recommended

(a) Discontinue at least

48 hours before elective surgery/invasive procedures with a moderate-high risk of clinically significant bleeding.

24 hours a low risk of bleeding.

(b) Anticoagulant effect lasts about 24 hours after the last dose.

(c) No antidote; not expected to be dialyzable


:

(a)2.5 mg orally twice daily when coadministered with strong dual inhibitors of CYP3A4 and Pgp (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin).

(b) AVOID if already taking 2.5 mg twice daily as well as a strong dual inhibitor of CYP3A4 and Pgp.

Avoid concomitant use of apixaban with strong dual inducers of CYP3A4 and Pgp (e.g., rifampin, carbamazepine, phenytoin, St. Johns wort).


a. FDA approved

b. Specific inhibitor of human thrombin

c. Structure similar to hirudin, the naturally occurring anticoagulant in the peripharyngeal glands of the medicinal leech

d. Indicated for DVT prophylaxis in patients undergoing elective hip replacement surgery

e. Dose: 15 mg subcutaneously every 12 hours; give initial dose 515 minutes before surgery. Duration of up to 12 days has been well tolerated.


Daily (aPTT) and Scr monitoring are; reduce dose if peak aPTT level exceeds 2 times control (after holding until aPTT returns to less than 2 times control).


Enoxaparin 30 mg SC q12h

Enoxaparin 40 mg SC q24h

Dalteparin 5000 units SC q24h

UFH 5000 units SC q8hq12hA.

: Surgery, major trauma, lower extremity injury, Immobility, malignancy, sepsis, heart failure, respiratory failure, venous compression, previous VTE, increasing age, pregnancy, ESA , obesity, and CVL.



11.A 75-year-old woman (height 65 inches, weight 68 kg) who is intubatedrequires mechanical ventilation for an acute exacerbation of chronic obstructive pulmonary disease. She has a medical history of heart failure and hypertension. Her laboratory values are normal except for a Cr of 1.9 mg/dL. Which is the most appropriate recommendation to prevent a VTE in this patient? A. Initiate intermittent pneumatic compression. B. Administer fondaparinux 2.5 mg subcutaneously once daily. C. Administer enoxaparin 30 mg subcutaneously once daily. D. Administer heparin continuous intravenous infusion to maintain an aPTTof 5070 seconds.

Ambulatory 2 Rad

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